Amidines and related compounds are known to exhibit anti-hypertensive properties as centrally acting anti-hypertensive agents. The overall action on blood pressure by the known amidine hypotensive agents such as clonidine, has been postulated to be the resultant of peripheral and central effects. The determination that the overall effect is a combination of peripheral and central action is based upon animal studies designed to separate these effects. Such studies are described, for example, by Rouot, LeClerk and Wermuth in the Journal of Medicinal Chemistry, 1976, Volume 19, No. 8.
Certain amidinoureas have been described as possessing blood pressure lowering effects in recently-issued patents. U.S. Pat. No. 4,088,785 discloses amidinoureas in which an amidino nitrogen is phenyl substituted having blood pressure lowering effects in the spontaneous hyperactive rat in tests done according to the method of Tabei et al, Clin. Pharm. and Therap. 11: 269-274, 1970. U.S. Pat. No. 4,117,165 discloses blood pressure lowering activity for amidinoureas in which a urea nitrogen is phenyl substituted and the amidino nitrogens are unsubstituted. In particular, this patent discloses that tests done according to the method of de Champlain et al, Circulation Research, xxii: 479 (1968), indicate anti-hypertensive properties for these compounds. U.S. Pat. No. 4,060,635, like U.S. Pat. No. 4,117,165, discloses phenyl substituted amidinoureas in which the phenyl substitution is on a urea nitrogen but which differ from those of U.S. Pat. No. 4,117,165 in that at least one of the amidino nitrogens is also substituted. The compounds are described as useful antidiarrheals without any indication of cardiovascular activity, particularly, hypotensive activity. Compounds of this class are also disclosed, and their properties described, in a monogram appearing in Arznemittel Forschung 28 (11), 1433-1480 (1978). At page 1463 of this monogram, it is disclosed that 1-(2'6'-dimethylphenyl)-3-methylamidinourea, a representative member of the compounds with substitution on an amidino nitrogen, also known as lidamidine, has little or no effect on blood pressure over a dose range of 0.1 to 1.0 mg/kg administered intravenously. Thus, from these prior art references, it appears that amidinoureas having phenyl substitution on one of the amidino nitrogens and amidinoureas having phenyl substitution on the urea nitrogen, without substitution on the amidino nitrogen, gave indications of effects on blood pressure in animal tests, whereas amidinoureas which have a phenyl substituent on the urea nitrogen and also substitution on at least one of the amidino nitrogens showed no significant effects on blood pressure in tests on animals. Surprisingly, applicant has now found that a dose-related effect on blood pressure in humans is obtained following administration of 1-(2'6'-dimethylphenyl-3-methylamidinourea in multiple daily doses.
Accordingly, it is an object of this invention to provide a novel method for lowering blood pressure in humans by administering a daily dose of an amidinourea in separate incremental amounts given periodically, thereby to achieve an effective level of active blood pressure lowering substance at the site of activity.